HOAt → N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3 aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide

HRID 511696Notes

Reaction equation

HRID 511696 reaction equation
[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:24]2)[O:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[F:67][C:68]([F:79])([F:78])[O:69][C:70]1[CH:71]=[C:72]([NH2:77])[C:73]([NH2:76])=[CH:74][CH:75]=1>C(Cl)Cl>[NH2:77][C:72]1[CH:71]=[C:70]([O:69][C:68]([F:67])([F:78])[F:79])[CH:75]=[CH:74][C:73]=1[NH:76][C:29](=[O:31])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1

Participants

6

Reactant 4

HCID 181649HOAtHCID 27739594-(Trifluoromethoxy)benzene-1,2-diamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 677751233-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid

Product 1

HCID 67777193N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3 aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamideYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.2 g, 2.91 mmol), HATU (2.17 g, 5.83 mmol) and HOAT (0.91 g, 5.83 mmol) in DCM (17 mL) were added 4-(trifluoromethoxy)benzene-1,2-diamine (1.1 g, 5.83 mmol) and TEA (2.05 mL, 14.56 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM (50 mL) and washed with water (15 mL×3) and brine (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (40 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume) to afford the desired compound (1.0 g, yield: 60%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.25-8.24 (m, 1H), 7.20-7.13 (m, 1H), 6.95-6.85 (m, 0.4H), 6.73 (brs, 0.8H), 6.54 (d, J=7.5 Hz, 0.8H), 6.22 (d, J=2.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.03-5.00 (m, 1H), 4.40-4.35 (m, 1H), 3.40-3.35 (m, 0.3H), 3.00-2.92 (m, 0.7H), 2.70-2.47 (m, 3H), 2.36-2.28 (m, 2H), 2.20-1.80 (m, 6H), 1.76-1.66 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H), 1.26-1.16 (m, 1H) ppm; ESI-MS (m/z): 621.3 [M+1]+.

Workup

  1. washwashed with water (15 mL×3) and brine (30 mL)
  2. dry with materialThe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by Combi-Flash (40 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume)

Sources & evidence

ORD record
ord-5272b4b886c14a1ab509f5b118903794
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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